Unearthing the mechanisms of responsive neurostimulation for epilepsy

Responsive neurostimulation (RNS) is an effective therapy for people with drug-resistant focal epilepsy. In clinical trials, RNS therapy results in a meaningful reduction in median seizure frequency, but the response is highly variable across individuals, with many receiving minimal or no benefit. Understanding why this variability occurs will help improve use of RNS therapy. Here we advocate for a reexamination of the assumptions made about how RNS reduces seizures. This is now possible due to large patient cohorts having used this device, some long-term. Two foundational assumptions have been that the device’s intracranial leads should target the seizure focus/foci directly, and that stimulation should be triggered only in response to detected epileptiform activity. Recent studies have called into question both hypotheses. Here, we discuss these exciting new studies and suggest future approaches to patient selection, lead placement, and device programming that could improve clinical outcomes.

Another study highlighting the importance of patient-specific functional connectivity for determining RNS efficacy used cortico-cortical evoked potentials to define receiver and projection nodesareas of greater inward or outward connectivity, respectivelyduring intracranial EEG monitoring in patients who were later treated with RNS 3 .[ Page 8]   We have also revised for clarity the statement on outcomes in this study: Clinical outcomes were significantly better when RNS electrodes were placed near receiver nodes.[ Page 8]   If we are fortunate enough to have our manuscript accepted, and if the study by Kobayashi and colleagues is published by then, we will include a citation to the published work.
3) It is expected that a greater proportion of the multidien cycle is spent in low-risk relative to high-risk states.Therefore, open-loop stimulation, which is impervious to the resting-state dynamics of the interictal epileptic network, should spend more time stimulating in low-than high-risk epochs of time.Since improved outcomes were noted when responsive stimulation was preferentially applied in low-risk states (reference #40, lines 156-159), one could speculate that open loop stimulation could have more neuromodulatory potential than closed loop stimulation although this is not borne out in the literature.I would be interested in the authors thoughts regarding this conundrum.
Response: We appreciate the Reviewers reasoning here and fully agree that this is a conundrum in the field, one for which we do not have an answer, owing mostly to the lack of controlled studies that compare different neurostimulation modalities/strategies head-to-head.Since Reviewer 2 also invoked a comparison between open-loop and closed-loop stimulation, we have added text and references to highlight this point: Indeed, chronic neuromodulatory effects help explain the similarity in outcomes between open-loop neurostimulation modalities [4][5][6] and closed-loop RNS 7 , and they call into question whether the effectiveness of RNS actually depends on its responsive nature.[ Page 10]   It was a pleasure to read this manuscript and its description of the transition from the traditional notion of seizure foci a notion still integral to the world of resective and ablative epilepsy surgery to an emphasis on epileptic network dynamics more applicable to the realm of neurostimulation and neuromodulation.
Response: We thank the Reviewer for these positive comments.

Reviewer: 2
This brief review is well-written and provides a helpful perspective for those seeking to understand or explain how RNS may work.Both authors are experts in the field and between the two of them have written widely about RNS, DBS, and Neurostimulation in general for epilepsy.
Overall, this review might benefit from somewhat more context within the field of Neurostimulation, which would make the article much more interesting to readers.The abstract highlights two foundational assumptions that are questioned (lead location and closed loop stimulation).However, the review itself does not seem to directly address the closed loop stimulation portion in comparison to open loop stimulation.For example, clinical results from DBS open loop devices are considered by most experts to be equivalent, and several studies exist comparing DBS with RNS (although retrospectively).In addition, there are studies dealing with open loop cortical stimulation for cortical stimulation (e.g Cukiert et al, 2017; Lundstrom et al, 2019) that seem to show similar results.How does this fit with the idea that stimulation must be responsive?It seems the closed loop aspect of RNS could readily be tested in RNS devices but never has been tested?In short, is it the case that the closed loop portion of the device has not been shown to be critical to its efficacy in any way?
Response: The Reviewer is correct that the responsive (closed-loop) nature of RNS, while appealing conceptually, has never been demonstrated to be critical for its efficacy.The closed-loop design of RNS stems from its original conception as a device for acute seizure termination, but, as we discuss at length, this is not likely to be its primary mode of action.The Reviewer is also quite right to point out that studies of open-loop neurostimulation modalities (we now cite the two studies suggested by the Reviewer, in addition to a study of long-term thalamic DBS outcomes by Salanova et al. ( 2021)) demonstrate outcomes that are similar to RNS, further casting doubt on the importance of closed-loop stimulation.However, it is not the case that the closed-loop aspect of RNS can be readily tested, because the device cannot be programmed to deliver stimulation in true open-loop fashion, thus precluding comparison of patients with open-loop vs. closed-loop RNS.In addition, head-to-head trials of different neurostimulation devices have not been done.
We have added the following text to incorporate these important points raised by the Reviewer: Indeed, chronic neuromodulatory effects help explain the similarity in outcomes between open-loop neurostimulation modalities [4][5][6] and closed-loop RNS 7 , and they call into question whether the effectiveness of RNS actually depends on its responsive nature.[Page 10] Related to this, the assumption that lead location is not critical would ideally also be addressed in the context of what is known about DBS devices, where lead localization has been more extensively studied and seem to be important, if not critical.
Response: We agree completely with the Reviewer that lead localization is critical.To harmonize recent studies on RNS lead targeting with the more extensive literature on DBS lead targeting, we have added the following text: This strategy dovetails with a larger body of evidence [8][9][10] indicating that precise lead targeting in relation to networks that involve thalamic nuclei is critical for the efficacy of deep brain stimulation (DBS) in epilepsy.

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Other comments: -L62: responder rate may need to be defined for readers; similarly meaningful improvement is not clear Response: We now define responder rate as the proportion of patients with 50% reduction in seizure frequency.We have also rephrased the second part of the sentence as: over a quarter of patients are not responders and may not experience worthwhile improvement with RNS.[Page 4] -L122-124 could benefit from an additional sentence to help clarify.It could be clearer how this fits with the prior logical flow of the review.
Response: We have added text to improve clarity and logical flow of this section: the effectiveness of RNS therapy seems to depend on intrinsic neurophysiological properties of seizures and the brain networks that give rise to them.For example, a speculative possibility is that interictal RNS stimulation can more readily diffuse through networks with high functional connectivity, which may potentiate its therapeutic effects, and that seizures less able to synchronize widespread networks are those most readily quelled by RNS stimulation.[Page 7] -L140: further clarity would be helpful Response: We have added text to clarify this concept: epileptic networks may have points of vulnerability where focal stimulation can exert high network controllability 11,12 and, conceivably, can suppress seizures as well or better than stimulation directly at the seizure onset zone.Identification of these critical pointsconceptually, the Achilles heels of epileptic networkscould inform RNS lead placement for optimal efficacy.[Page 8] -L162: some of these issues have been recently addressed and reference could be helpful to Frauscher et al, Epilepsia 2023 Response: We thank the Reviewer for this suggestion, and we now cite this excellent work by Frauscher and colleagues.
Thus, observed outcomes may underestimate the potential of RNS therapy by reflecting the net of potentially opposing effects during network state cycling 13 .[Page 9] -Emerging Model section would ideally contain clearer, distinct conclusions that summarize what was previously presented Response: Our hope was the infographic Figure would serve to distill key conclusions from the studies that were reviewed.We have made some aesthetic improvements to this Figure for greater clarity and visual appeal.In addition, we have added the following sentence to this section to try and capture the essential sentiment of this perspective piece: Recent studies have revealed that one size does not fit all for epilepsy neurostimulation therapies, which need to be as diverse and dynamic as brain networks themselves.[Page 11] -L205: palliative therapies would be more palatable if they worked faster does DBS (with similar results) work faster?
Response: We mention that RNS and DBS both take years to maximally reduce seizures, and clinical trial publications cited in the manuscript suggest comparable timecourses for improvement.We are not aware of data showing that DBS works more quickly than RNS.
-Perhaps an oversight related to competing interests?Both authors seem to have recently reported relevant disclosures.We are grateful for a third round of Reviewer feedback on our manuscript and for the opportunity to revise and resubmit it for consideration of publication as a Perspective in Communications Medicine.

Response
Please find below our point-by-point responses to the Reviewers concerns.The original concern is shown in italics.Our responses are shown in blue.All page numbers listed refer to pages on the manuscript version with tracked changes.

Reviewer: 2
Thank you for the attention to these comments.
The newly cited reference regarding open vs closed loop stimulation may not make sense in the context of this human RNS review since in the rodent example the closed-loop stimulation seems to work by stopping seizures, which the review authors already argue is not likely the way RNS works.If RNS worked by stopping seizures, then clearly tuning to seizure onset would affect outcome.So the new citation may be a bit of a red herring with a possible tendency to mislead the reader.
Response: Thank you for pointing this out.We have removed the citation 1 from this section [Page 12] to avoid possibly animal model studies are also cited.
Also if the authors would define "and other valuable diagnostic data from the device", that would be helpful to the reader.As it is the vast majority of stimulations do not occur at the onset of the seizures.

Response:
he citation 2 that in sentence is a review article that covers applications of RNS data, including seizure quantification.I will leave these two points to discretion of the authors.Thank you for your careful consideration of this important aspect of stimulation for epilepsy.I agree with Reviewer 1: "It was a pleasure to read this manuscript and its description of the transition from the traditional notion of seizure foci a notion still integral to the world of resective and ablative epilepsy surgery to an emphasis on epileptic network dynamics more applicable to the realm of neurostimulation and neuromodulation." Response: We appreciate the positive comments and critical feedback, and we thank the Reviewer for their time.

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We have added a Competing Interests Statement to declare our prior roles as consultants for NeuroPace, Inc. and our ongoing involvement as investigators in the NIH-funded RNS-LGS Feasibility Study (NCT05339126).[Page 12] Manuscript No.: COMMSMED-23-0533B Title: Unearthing the mechanisms of responsive neurostimulation for epilepsy Corresponding Author: Vikram Rao Response to Referee comments: